The overall goal of this project to develop protein-based reagents for the targeted immunosuppression of human multiple sclerosis. These reagents will consist of novel recombinant single-chain (sc) forms of the class II/peptide complex designed to target autoreactive T helper cells. Our approach for generating these molecules is innovative in that the nature of the class II/peptide complex can be readily manipulated to alter T cell responses and that large amounts of homogeneous and well-defined molecules can be produced. To achieve our goal, we will clone and express different classes of genetically altered soluble sc-MHC class II/peptide fusion molecules. A number of these molecules are currently being produced in our laboratory. The immunosuppressive properties of these molecules will be tested in activation and anergy assays using mouse T cells and T cells isolated from MS patients. The molecules will also be tested for their ability to effect the initiation and differentiation of Th1 and Th2 responses and T cell-mediated autoimmune disease (EAE) in animal model systems. The results from these studies will provide useful information regarding immunosuppressive potential of the sc-MHC and will be useful in determining their efficacy in treating human T-cell mediated autoimmune diseases. PROPOSED COMMERCIAL APPLICATIONS: The goal of this proposal is to establish whether or single-chain MHC class II/peptide molecules are effective in specifically suppressing T-cell mediate immune responses in vitro and in antigen-immunized and autoimmune mouse model systems. The results of these studies could be used as a basis a therapeutic approach for treating human T cell-mediated autoimmune diseases, such as multiple sclerosis.